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 Table of Contents  
SYSTEMATIC REVIEW
Year : 2021  |  Volume : 40  |  Issue : 1  |  Page : 39-69

Auditory and cognitive functioning in hidden hearing loss due to noise exposure, aging, and tinnitus: A systematic review


Department of Audiology, All India Institute of Speech and Hearing, Mysuru, Karnataka, India

Date of Submission04-Feb-2022
Date of Acceptance12-Jul-2022
Date of Web Publication06-Sep-2022

Correspondence Address:
Dr. Sahana Vasudevamurthy
Department of Audiology, All India Institute of Speech and Hearing, Mysuru 570006, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jose.JOSE_2_22

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  Abstract 

Purpose: Since the inception of the term cochlear synaptopathy, extensive research is carried out to study the effects of noise and age on suprathreshold hearing in individuals with otherwise normal hearing. Yet, there is a lack of a standard test battery. We hypothesize that this variability in the results across studies may be due to the use of “cochlear synaptopathy” or “hidden hearing loss” as a blanket term to refer to auditory deficits seen in individuals with noise exposure, aging, and tinnitus with normal hearing. The present study aimed to systematically review the literature on hidden hearing loss due to noise exposure, aging, and tinnitus. Method: Keywords were combined using Boolean operations, and an electronic search was carried out through PubMed, ScienceDirect, ResearchGate, and Google Scholar databases. Screening for abstracts, title, and full text resulted in 46 articles eligible for data extraction. Results: Among the 46 studies considered for the review, 30 studies included human participants and 16 included animal participants. The possibility of noise-induced synaptopathy was assessed in 30 studies; age-induced synaptopathy in 6 studies; and synaptopathy in normal-hearing individuals with tinnitus in 10 studies. The results revealed conclusive findings of synaptopathy in animals; however, the evidence in studies involving human participants was inconclusive. Conclusions: Auditory brainstem response (ABR), histopathology, and middle ear muscle reflex (MEMR) are the widely used measures of synaptopathy in animals. Human studies indicated that temporal processing, speech perception in the presence of background noise, and working memory are majorly affected in individuals with hidden hearing loss. Specifically, speech perception in noise (SPiN), temporal resolution, MEMR, ABR wave I amplitude growth, and electrocochleography (ECochG) are identified as the potential measures of hidden hearing loss due to noise exposure. Further, the effect of common recreational noise on these measures is less compared to high life-time noise exposure. The results of synaptopathy due to aging or tinnitus are inconclusive.

Keywords: Cochlear synaptopathy, cognition, hidden hearing loss, suprathreshold hearing, systematic review


How to cite this article:
Vasudevamurthy S, Kumar AU. Auditory and cognitive functioning in hidden hearing loss due to noise exposure, aging, and tinnitus: A systematic review. J All India Inst Speech Hear 2021;40:39-69

How to cite this URL:
Vasudevamurthy S, Kumar AU. Auditory and cognitive functioning in hidden hearing loss due to noise exposure, aging, and tinnitus: A systematic review. J All India Inst Speech Hear [serial online] 2021 [cited 2022 Oct 3];40:39-69. Available from: http://www.jaiish.com/text.asp?2021/40/1/39/355662




  Introduction Top


Sensorineural hearing loss is the most prevalent form of hearing impairment in adults. Dysfunctional outer hair cells (OHCs), inner hair cells (IHCs), auditory nerve fibers or synapses between IHCs, and auditory nerve fibers are the major causes of sensorineural hearing loss. Traditionally, an individual’s hearing sensitivity is measured using pure tone audiometry. Typically, sensorineural hearing loss results in elevated hearing thresholds and can be detected by pure tone audiometry. It is becoming increasingly evident that all types of hearing loss cannot be predicted based on the audiogram (Plack et al., 2014). Many individuals who visit the audiology clinic with tinnitus or difficulty understanding speech in noise are often diagnosed with normal hearing sensitivity. This leaves them often unsatisfied since they have clinically normal hearing yet experience difficulty in real-life situations. Animal studies suggest that noise or age-induced synaptopathy may explain some of the suprathreshold hearing deficits seen in individuals with normal hearing (Bakay et al., 2018; Cai et al., 2018; Chen et al., 2019; Muniak et al., 2018; Song et al., 2016).

In a seminal study, Kujawa and Liberman (2009) reported that traumatic noise exposure resulted in permanent loss of 50% of the synapses between IHC and auditory nerve fibers, despite the recovery of lost hair cells. As a result, although the ABR threshold recovered completely, the amplitude of ABR wave I at suprathreshold level was reduced; indicating a permanent suprathreshold deficit. This neural degeneration reduces the number of low spontaneous rate fibers that codes for moderate to high intensity sounds. Hence, synaptopathy does not elevate the behavioral or electrophysiological thresholds despite the possibility of suprathreshold deficits (Furman et al., 2013; Liberman et al., 2016). This form of hearing problem remains hidden as the clinically used pure tone audiometry or electrophysiological threshold measures are insensitive to suprathreshold deficits (Liberman et al., 2016) and has been referred to as cochlear synaptopathy (Kujawa & Liberman, 2009) or hidden hearing loss (Schaette & McAlpine, 2011). Subsequently, cochlear synaptopathy was shown in other species such as guinea pigs (Chen et al., 2019; Mulders et al., 2018; Song et al., 2016), chinchillas (Hickman et al., 2018), and rhesus monkeys (Valero et al., 2017). A similar reduction in the number of ribbon synapses has been reported as a consequence of aging (Muniak et al., 2018; Parthasarathy & Kujawa, 2018; Sergeyenko et al., 2013). Although cochlear synaptopathy can be directly evidenced through histology in animals, the same is not feasible in humans. Thus, studies on humans depend on indirect or proxy measures of cochlear synaptopathy (Bharadwaj et al., 2019; Bramhall et al., 2019; Guest et al., 2019; Plack et al., 2016). Over the past decade, various behavioral and electrophysiological measures used to assess cochlear synaptopathy are reported in the literature. The most commonly reported electrophysiological measures are ABR, ECochG, and envelope following responses (EFRs). The behavioral measures investigated include speech perception in noise (SPiN), gap-detection thresholds (GDTs), and modulation detection. However, a reliable diagnostic test does not exist as yet. This is attributed to the lack of reliability of the possible direct measures of synaptopathy (ABR wave I amplitude) or the effect of central processes on the indirect behavioral measures of synaptopathy (Plack et al., 2016). A review by Barbee et al. (2018) described the various diagnostic tools and their effectiveness in identifying cochlear synaptopathy in humans and animals. They concluded that sensitive measures of cochlear synaptopathy are amplitude of ABR wave I, the summating potential to action potential ratio, and speech recognition in noise. However, Barbee et al. (2018) did not include age-induced cochlear synaptopathy in their review. In addition, literature on cochlear synaptopathy is growing rapidly and a simple PubMed search with keywords “hidden hearing loss” or “cochlear synaptopathy” resulted in 138 peer-reviewed articles on this topic since 2018.

Despite the spurt in the literature on cochlear synaptopathy in the past decade, there is no consensus about the diagnostic test battery for the same. Results of different auditory tests are highly variable between studies. For example, Bramhall et al., (2017) reported reduced wave I amplitude in individuals at risk for cochlear synaptopathy whereas Guest et al. (2017) did not find a difference in wave I amplitude between individuals with high and low risk for cochlear synaptopathy. We hypothesize that this variability in the results across studies may be because of the use of “cochlear synaptopathy” or “hidden hearing loss” as a blanket term to refer to auditory deficits due to a variety of causes such as noise exposure, aging, and tinnitus in the presence of normal hearing. The pathophysiology caused by each of these conditions may be different, resulting in equivocal results. Hence, reviewing the literature on hidden hearing loss or synaptopathy due to noise exposure, aging and tinnitus is essential to understand if each of these factors has different effects on various auditory and cognitive skills. Further, the review will also highlight the use and effectiveness of various measures in identifying hidden hearing loss caused due to the aforementioned causes. Therefore, the purpose of this systematic review is to document and classify the current, peer-reviewed research evidence about the

  1. effect of noise exposure on auditory and cognitive capacities in individuals with normal hearing sensitivity


  2. effect of aging on auditory and cognitive capacities in individuals with normal hearing sensitivity


  3. auditory and cognitive capacities in normal-hearing individuals with tinnitus


  4. effectiveness of various auditory and cognitive measures in identifying hidden hearing loss caused due to noise exposure, aging, and tinnitus


The results of this review will encapsulate the effects of cochlear synaptopathy or hidden hearing loss on various auditory skills and the tests used to assess the same.


  Methods Top


This study aimed at reviewing the published literature on hidden hearing loss or cochlear synaptopathy.

Inclusion criteria

Study types

Experimental studies on hidden hearing loss or cochlear synaptopathy were included from the literature search.

Participant details

The literature search included articles with humans or animals as study participants. There were no restrictions in terms of the age and gender of the participants. The studies that included older adults with normal hearing, young normal-hearing individuals with a history of noise exposure or tinnitus as participants were considered for the review.

Investigation details

Any diagnostic protocol (behavioral or electrophysiological) intended to assess auditory skills were considered. All relevant articles published till May 2020 were considered for the review.

Exclusion criteria

Study types

Conference papers, review articles, book chapters, and documents were excluded from the search.

Participant details

Individuals with hidden hearing loss due to any factors other than noise exposure, aging, and tinnitus were excluded from the search.

Search strategy

PubMed, ScienceDirect, ResearchGate, and Google Scholar were used for the literature search. The keywords cochlear synaptopathy, hidden hearing loss, and cochlear neuropathy were combined with appropriate Boolean operations to search for relevant literature. The search string used in PubMed is given below as an example.

PubMed

([“cochlear synaptopathy”] OR [“hidden hearing loss”] OR [“cochlear neuropathy”])

The title, abstract and full-text of the articles were independently read by both authors to finalize on their inclusion in the review. Any disagreements were resolved with mutual consensus or the advice of the second author. The per cent agreement in sifting and quality assessment of the articles were 83.6 and 100, respectively.

Quality assessment

The articles included for the review were assessed for the presence of any bias on the basis of the following questions:

  • Q1: Were the aims and objectives clearly defined?


  • Q2: Were the participant details, inclusion, and exclusion criteria clearly stated?


  • Q3: Were the variables and study procedures described in detail?


  • Q4: Were the investigators blinded to participant details?


  • Q5: Were the measured outcomes clearly described?


  • Q6: Were the reasons for dropouts clearly mentioned?


  • A rating of 1 was given when the answer to the above questions was “yes”; and 0 when the answer was “no/not reported.”


      Results Top


    Study flow

    The literature search and retrieval process followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. [Figure 1] shows the PRISMA chart. Multiple databases were used for the search viz. PubMed, ScienceDirect, ResearchGate, and Google Scholar, and the search from these databases resulted in 536 records. The next step involved the removal of duplicates, which resulted in 199 articles eligible for further screening. In addition, five articles were included in the reference list of the selected articles.
    Figure 1: PRISMA chart illustrating the study selection and retrieval process

    Click here to view


    These records were screened for title and abstract. Sixty-eight articles were removed as the titles did not match the inclusion criteria while screening of abstracts and non-availability of full-text result led to the exclusion of 71 and 10 articles, respectively. Thus, a total of 55 articles were eligible for the full-text review. At this stage, nine articles were discarded as they were not within the scope of this review. Of those nine articles, a few were excluded as the participants included had no obvious signs of cochlear synaptopathy or hidden hearing loss and only reliability of the proxy measures were assessed on normal-hearing individuals, whereas the others were excluded as they used models or simulations to describe cochlear synaptopathy. At the end of the full-text review, 46 articles were found to be eligible and were therefore included in the qualitative synthesis. The articles were divided into three categories viz. noise-induced synaptopathy, age-induced synaptopathy, and synaptopathy in individuals with tinnitus. A summary of all the eligible studies is provided in Appendix 2.

    Quality assessment

    Quality appraisal was carried out for all the included studies. The level of interrater agreement between authors for appraisal of study quality was 100. The quality appraisal ratings ranged from 4 to 6. Except for Smith et al. (2019), none of the studies had the investigators blinded to participant details. The quality appraisal for human studies and animal studies is included in Appendix 3.

    Participant characteristics

    Of the 46 articles included for qualitative synthesis, six investigated age-induced synaptopathy, 30 investigated noise-induced synaptopathy and the remaining ten articles investigated auditory behavior in normal-hearing individuals with tinnitus. Further, 30 studies involved human participants, and 16 studies involved animal participants. The age range for human participants was between 18 and 80 years and for animals between 4 and 128 weeks. Studies investigating noise-induced cochlear synaptopathy in animals performed auditory assessments pre- and post-noise exposure. However, such noise exposure was not a part of human studies. Instead, a history of noise exposure was analyzed retrospectively using questionnaires, interviews, or self-reports. The auditory skills assessed in the studies can be grouped under four domains namely behavioral, physiological, electrophysiological, and cognitive.

    Human studies

    Noise-induced synaptopathy

    A total of 17 studies addressed the issue of noise-induced synaptopathy in human subjects. Majority of the studies (14) used self-reports, questionnaires or structured interviews to document the noise exposure among their participants. The participants were asked to record their lifetime noise exposure details using various questionnaires such as Noise Exposure Structured Interview (NESI), Lifetime Exposure to Noise and Solvents Questionnaire (LENS-Q). They were asked to identify the noise events (occupational/recreational); they were involved in determining the duration of noise exposure based on the frequency of occurrence and the level of noise based on the vocal effort required in conversation. A few other questionnaires dealt with domains such as noise exposure, tinnitus, and SPiN. Based on the scores obtained using these questionnaires or interviews, the participants were divided into either high-noise exposure/high-risk group or low-noise exposure/low-risk group. The specific details of noise exposure (such as intensity and duration of exposure) in the study participants were reported in only three studies. The differences in the methodology used to categorize the participants into different groups may have contributed to the variability in the results among studies. The human studies on noise-induced synaptopathy have focused on the relationship between lifetime noise exposure scores and auditory performance as assessed through behavioral or physiological tests.

    Among the behavioral tests, thresholds in quiet at extended high frequencies was assessed in five studies (Bramhall et al., 2017; Liberman et al., 2016; Marmel, Perugia, & Kluk, 2018; Prendergast et al., 2017; Smith et al., 2019); SPiN was evaluated in 11 studies (Fulbright et al., 2017; Grinn et al., 2017; Grose et al., 2017; Guest et al., 2018; Guest et al., 2019; Liberman et al., 2016; Maruthy et al., 2018; Prendergast, et al., 2017; Smith et al., 2019; Valderrama et al., 2018; Yeend et al., 2019) and thresholds in noise or the effect of masking was investigated in two studies (Bharadwaj et al., 2015; Yeend et al., 2019). Differential sensitivity of frequency, intensity, duration, or phase were measured in three studies (Bharadwaj et al., 2015; Grose et al., 2017; Prendergast, et al., 2017). Binaural interaction abilities were evaluated in one study (Prendergast, et al., 2017), and temporal or spectral resolution in terms of modulation detection was measured in five studies (Bharadwaj et al., 2015; Grose et al., 2017; Kumar et al., 2012; Prendergast, et al., 2017; Yeend et al., 2019) and GDT was measured in one study (Kumar et al., 2012). Although temporal integration was examined in two studies (Marmel et al., 2018; Fulbright et al., 2017), duration pattern was assessed in one study (Kumar et al., 2012).

    Physiological assessment of humans involved recording otoacoustic emissions and middle ear muscle reflexes (MEMR). Cochlear functioning was assessed by measuring distortion product otoacoustic emissions (DPOAE) in most studies. Although DPOAE input–output function was used in three studies (Bharadwaj et al., 2015; Bramhall et al., 2017; Grose et al., 2017), DP gram (DPOAE across various f2) was measured in seven studies (Fulbright et al., 2017; Grinn et al., 2017; Grose et al., 2017; Liberman et al., 2016; Smith et al., 2019; Valderrama et al., 2018; Yeend et al., 2019). Prendergast, et al. (2017) evaluated the cochlear functioning using transient evoked otoacoustic emissions (TEOAE). Functioning of the middle ear and the auditory nerve was evaluated by measuring MEMR in one study (Guest et al., 2019).

    Various electrophysiological measures at the level of the cochlea, brainstem, and auditory cortex were performed on humans. ECochG was performed in two studies to assess cochlear functioning (Grinn et al., 2017; Liberman et al., 2016), Auditory brainstem response (ABR) was recorded in seven studies (Bramhall et al., 2017; Fulbright et al., 2017; Grose et al., 2017; Guest et al., 2018; Prendergast, et al., 2017; Smith et al., 2019; Valderrama et al., 2018) and EFR or frequency following response (FFR) was recorded in six studies (Bharadwaj et al., 2015; Bressler et al., 2017; Grose et al., 2017; Guest et al., 2018; Marmel et al., 2018; Prendergast et al., 2017).

    Cognitive assessment was carried out on human subjects with suspected noise-induced synaptopathy. Attention abilities were assessed in five studies (Bharadwaj et al., 2015; Bressler et al., 2017; Guest et al., 2018; Valderrama et al., 2018; Yeend et al., 2019), and working memory was evaluated in two studies (Maruthy et al., 2018; Yeend et al., 2019) using various tests.

    Age-induced synaptopathy

    A fewer number of studies (3) addressed the issue of age-induced cochlear synaptopathy compared to noise-induced synaptopathy in human subjects. The studies on age-induced synaptopathy in humans have assessed modulation detection and masked thresholds under behavioral domain as against various psychophysical tests (duration pattern test, SPiN, GDT, high-frequency audiometry) utilized in the case of noise-induced synaptopathy. Interaural phase difference was assessed by Prendergast et al. (2019). Temporal and spectral resolution in terms of modulation detection was assessed in two studies (Grose et al., 2019; Prendergast et al., 2019). Although ABR was recorded in two studies (Grose et al., 2019; Prendergast et al., 2019), EFR was recorded in one study (Prendergast et al., 2019) on age-induced synaptopathy.

    Synaptopathy in individuals with tinnitus

    Ten studies evaluated the possibility of synaptic damage in normal hearing individuals with tinnitus. Hearing threshold at extended high-frequency SPiN was assessed in normal-hearing individuals with tinnitus by Kara et al. (2020). High-definition audiometry was administered by Lefeuvre et al. (2019), differential sensitivity in the domain of intensity was assessed by Epp et al., (2012) and the threshold equalizing noise (TEN) test was administered in two studies (Kara et al., 2020; Marmel et al., 2020). Temporal resolution in terms of modulation detection was measured by Paul et al., (2017), whereas temporal integration was assessed by Marmel et al. (2020). In the physiological domain, DP gram was measured in three studies (Kara et al., 2020; Marmel et al., 2020; Xiong et al., 2019) and MEMR was measured in one study (Wojtczak et al., 2017). In the electrophysiological domain, ECochG was performed in one study (Kara et al., 2020), ABR in three studies (Guest et al., 2017; Schaette and McAlpine, 2011; Shim et al., 2017) and EFR in two studies (Guest et al., 2017; Paul et al., 2017).

    Animal studies

    Noise-induced synaptopathy

    In animals, DPOAE input–output function was evaluated in seven studies (Fernandez et al., 2020; Hickman et al., 2018; Lobarinas et al., 2017; Morgan et al., 2019; Shaheen et al., 2015; Valero et al., 2016; Valero et al., 2018), DP gram in two studies (Song et al., 2016; Valero et al., 2017) and MEMR was measured in two studies (Valero et al., 2016, Valero et al., 2018). In the electrophysiological domain, whereas ABR was recorded in most of the studies (Bakay et al., 2018; Chen et al., 2019; Fernandez et al., 2020; Hickman et al., 2018; Liu et al., 2019; Lobarinas et al., 2017; Morgan et al., 2019; Mulders et al., 2018; Shaheen et al., 2015; Song et al., 2016; Valero et al., 2016, 2018; Valero et al., 2017), EFR was recorded in one study (Chen et al., 2019).

    Age-induced synaptopathy

    DP gram and EFR was recorded in one study (Parthasarathy & Kujawa, 2018), whereas ABR was recorded in three studies (Cai et al., 2018; Muniak et al., 2018; Parthasarathy & Kujawa, 2018).


      Discussion Top


    This systematic review identified 40 studies that were not included as a part of the systematic review on hidden hearing loss performed by Barbee et al. (2018). The findings of the review will be discussed with regard to noise-induced synaptopathy, age-induced synaptopathy, and synaptopathy in individuals with tinnitus. Under each of these sections, the results of studies carried out on humans will be discussed with respect to behavioral domain, physiological domain, electrophysiological domain, and cognitive domain whereas animal studies will be discussed with respect to physiological and electrophysiological domains. It should, however, be noted that the examiners of only one study were blinded to participant details. Further, none of the studies were double-blinded or randomized control trials. Therefore, there is a need to conduct studies using more robust methodologies such as randomized control trials to draw stronger conclusions.

    Human studies

    Noise-induced synaptopathy

    Behavioral domain

    Hearing thresholds at extended high frequencies can predict damage to OHCs at an early stage compared to conventional pure tone audiometry (Mehrparvar et al., 2011). Several studies have performed extended high-frequency audiometry on individuals at risk for noise-induced synaptopathy. Five studies compared extended high-frequency audiometry results between individuals at low risk and high risk for cochlear synaptopathy. Individuals were divided into low-risk or high-risk groups based on self-report of noise exposure and scores obtained on questionnaires. The critical finding of these studies is that the hearing thresholds assessed at extended high frequencies are affected in individuals at high risk for cochlear synaptopathy. A few studies explored the relationship between extended high-frequency hearing thresholds and SPiN (Liberman et al., 2016; Smith et al., 2019). Two studies were conducted to examine if any association existed between high-frequency audiometry and FFR (Marmel et al., 2018; Prendergast et al., 2017). Though the extended high-frequency hearing thresholds were elevated in the high-risk group (for cochlear synaptopathy), there was no correlation between the thresholds and the performance on SPiN or FFR.

    Many individuals with normal audiograms face difficulty perceiving speech in real-life situations. Most of the studies investigating cochlear synaptopathy or hidden hearing loss have assessed SPiN using various stimuli (syllables, words, phrases and sentences) and maskers (multi-talker babble, speech noise and broadband noise). Equivocal findings are reported about the perception of SPiN as a measure of hidden hearing loss. In individuals with suspected noise-induced synaptopathy, six studies reported reduced SPiN scores. Among these, four studies found SPiN skills to be correlated with other measures of synaptopathy (Kumar et al., 2012; Maruthy et al., 2018; Valderrama et al., 2018; Yeend et al., 2019), whereas two studies failed to show such correlation (Guest et al., 2018; Liberman et al., 2016). However, another set of studies showed that SPiN score was not affected in individuals at high risk for noise-induced hidden hearing loss (Fulbright et al., 2017; Grinn et al., 2017; Grose et al., 2017; Prendergast et al., 2017; Smith et al., 2019). The variability in the results among different studies can be accounted, in part, for the type of noise exposure. In most studies that reported poor SPiN scores, participants had exposure to occupational noise or high lifetime noise exposure. On the contrary, participants of studies that reported normal SPiN scores had exposure to recreational noise. Participants in Grinn et al. (2017) and Grose et al. (2017) were exposed to loud recreational events and later assessed for their SPiN abilities. Though the participants were exposed to multiple loud recreational events, the effect of this recreational noise exposure on SPiN was minimum when compared to occupational noise exposure (measured using SLM) or high lifetime noise exposure (assessed using noise survey).

    Many studies have investigated the effect of noise exposure on a range of psychophysical tasks for listeners with normal audiograms. There is some evidence that individuals at high risk for cochlear synaptopathy show deficits in temporal processing (Bharadwaj et al., 2015; Kumar et al., 2012). Kumar et al. (2012) observed that GDT was significantly affected in normal-hearing individuals with occupational noise exposure. They also reported that GDT is a good predictor of SPiN. Bharadwaj et al. (2015) reported poorer amplitude modulation detection threshold and envelope – interaural time difference (ITD) sensitivity in individuals with greater noise exposure than less noise exposure. In contrast, no differences in the psychophysical tuning curve (PTC) at 4000 Hz (Bharadwaj et al., 2015), difference limen for intensity (DLI) (Prendergast, et al., 2017) and difference limen for frequency (DLF) (Prendergast et al., 2017) have been reported between individuals at high and low risk for cochlear synaptopathy. Similarly, other investigators have reported no effect of noise exposure (as measured through self-report or questionnaires) on several psychophysical measures: interaural phase difference discrimination (Grose et al., 2017; Prendergast et al., 2017; Prendergast et al., 2019), amplitude modulation detection (Grose et al., 2017, 2019; Prendergast et al., 2017; Yeend et al., 2019), temporal integration (Fulbright et al., 2017; Marmel et al., 2018) and TEN test (Yeend et al., 2019).

    Physiological domain

    Majority of the studies have used DPOAE to evaluate cochlear functioning. Since cochlear synaptopathy refers to the damage in the synapse between the IHCs and the auditory nerve, cochlear amplification at the level of OHCs is expected to be normal. The experiments carried out on human participants reported that the OAE amplitudes in individuals with suspected noise-induced synaptopathy, age-induced synaptopathy, and individuals with tinnitus were similar to those of the control group. Hoben et al. (2017) evaluated the relationship between the functioning of OHCs and speech perception in individuals with normal hearing and hearing loss. OHCs functioning, as measured through DPOAE amplitudes and thresholds, was significantly correlated with the speech perception measures, especially near thresholds. Persons with poorer word recognition scores near the speech recognition threshold had more robust DPOAE responses than those with better word recognition scores. Hoben et al. (2017) concluded that OHC dysfunction contributes to hidden hearing loss or cochlear synaptopathy, especially at a lower intensity.

    The functioning of the middle ear and the auditory nerve was evaluated by measuring the MEMR in one study carried out on human participants with suspected noise-induced synaptopathy. Wojtczak et al. (2017) reported reduced MEMR amplitude in normal-hearing individuals with noise-induced tinnitus.

    Electrophysiological domain

    The functioning of the auditory pathway was evaluated at the level of the cochlea, brainstem, and auditory cortex through various evoked potentials. At the cochlear level, ECochG was performed. It is hypothesized that the summating potential (SP), primarily generated by hair cells would be unaltered and the action potential (AP), generated by auditory nerve fibers would be affected in cochlear synaptopathy. Thus, an increase in SP/AP ratio is expected in cochlear synaptopathy. Liberman et al. (2016) reported an increased SP/AP ratio in individuals at risk for cochlear synaptopathy. In contrast, Grinn et al. (2017) reported normal SP/AP ratio in individuals exposed to loud recreational noise. They opine that the risk of synaptopathy due to common recreational noise is lesser than occupational noise. The ECochG findings must be interpreted along with OHC functioning when suspecting cochlear synaptopathy accompanied by hearing loss. In general, if interpreted carefully with due consideration to the variability in SP, the SP/AP ratio can be a potential indicator of cochlear synaptopathy.

    Results of ABR testing in humans have yielded mixed results. A few studies report abnormal findings in ABR due to noise exposure (Bramhall et al., 2017; Grose et al., 2017; Valderrama et al., 2018). Bramhall et al. found that suprathreshold wave I amplitude was reduced in veterans reporting a high level of military noise exposure. Grose et al. reported abnormal wave I/ V amplitude ratio in individuals exposed to loud recreational noise. Valderrama et al. reported a significant negative correlation between self-reported life-time noise exposure levels and the amplitude of wave I of ABR. In contrast, others have reported no evidence of noise-induced synaptopathy in ABR findings (Fulbright et al., 2017; Guest et al., 2018; Prendergast, et al., 2017; Smith et al., 2019). In animal models, reduced compound action potential (wave I of ABR) is consistent with the cochlear synaptopathy. However, the results from human listeners are equivocal. This may be primarily attributed to two reasons: (a) In animals, the compound action potentials are measured pre and post loud noise exposure. On the contrary, noise exposure was estimated through retrospective self-reports or structured interviews in most human studies. It is plausible that retrospective self-report may not reliably capture the noise exposure. (b) Although the amplitude of compound action potential in animals was measured using intratympanic or ear canal electrodes, wave I was recorded using scalp electrodes in majority of the human studies. It is well known that the wave I amplitude is lesser (Bauch & Olsen, 1990; Yanz & Dodds, 1985), and variability is higher in far-field recordings compared to near field recordings (Bieber et al., 2020). It is interesting to note that all the three studies included in this systematic review that reported reduced wave I amplitude in individuals at high risk for cochlear synaptopathy recorded the ABR using tiptrode electrodes placed in the ear canal. Therefore, it appears that recording montage is critical while recording ABR in individuals at risk for noise-induced cochlear synaptopathy.

    FFR is known to reflect the neural temporal coding (Plack et al., 2014) and is correlated with SPiN (Song et al., 2011) and behavioral frequency discrimination (Marmel et al., 2013). Since noise exposure has adverse effects on temporal processing as revealed through behavioral measures; the same is expected to be evident through FFR or ERF. A few human studies on noise-induced synaptopathy (Bharadwaj et al., 2015) and tinnitus (Paul et al., 2017) reveal that the neural temporal coding is affected in individuals with cochlear synaptopathy and the same is reflected in EFR. However, majority of the studies failed to provide evidence of cochlear synaptopathy using EFR (Bressler et al., 2017; Grose et al., 2017; Guest et al., 2017, 2018; Marmel et al., 2018; Prendergast et al., 2017; Prendergast et al., 2019).

    Cognitive domain

    Speech perception involves the interplay between auditory and cognitive process (Füllgrabe & Rosen, 2016). Cognitive processing, specially the working memory, plays a vital role in perception of speech in adverse listening conditions (Akeroyd, 2008). According to Ease of language understanding (ELU) model (Rönnberg et al., 2008), working memory plays an important role when there is a mismatch between the speech input and the stored phonological representation. This mismatch affects automatic comprehension of the spoken word, thereby necessitating effortful processing involving working memory to perceive the same. Therefore, cognitive processing is an essential component of speech perception in adverse listening conditions even in individuals with normal hearing abilities.

    Noise affects not only hearing but also cognition. In this regard, a few studies have attempted to investigate the cognitive skills, mainly working memory and attention, in individuals suspected to have hidden hearing loss. Of the five studies that evaluated attention abilities using various tests, two studies illustrated poor attention abilities in individuals with higher life-time noise exposure with otherwise normal hearing (Bharadwaj et al., 2015; Bressler et al., 2017). In contrast, Guest et al. (2018) did not find a significant difference in the attention skills of individuals with reduced SPiN at risk for noise-induced synaptopathy. This could be attributed to the difference in the test used. Guest et al. (2018) used the Trial Making test, which assesses psychomotor speed, visual search, and mental flexibility. However, earlier studies have shown that noise exposure predominantly affects working memory than other cognitive domains. The results of studies on cochlear synaptopathy must be interpreted with caution as attention was reported to significantly influence other tasks such as SPiN (Valderrama et al., 2018; Yeend et al., 2019). Further, working memory was considered a good predictor of SPiN scores by Yeend et al. (2019). Maruthy et al. (2018) also reported that working memory was affected in individuals with possible hidden hearing loss, although it does not significantly facilitate SPiN. On the whole, findings on cochlear synaptopathy must be interpreted cautiously by considering the effect of cognition on various behavioral tasks.

    From the above discussion, it is can be inferred that the results of various tests are equivocal in individuals with noise-induced synaptopathy. We hypothesize that one of the major factors contributing to this heterogeneity is the lack of precise documentation of noise exposure. Majority of the studies have used questionnaires, self-reports and interview to classify humans “at-risk” for noise-induced synaptopathy. These subjective measures might not capture the actual noise exposure history. However, based on the findings of various studies, it can be concluded that SPiN, GDT, MEMR, and ABR wave I amplitude are sensitive to identify individuals who are at risk for noise-induced synaptopathy. These results are also in consensus with the results of the systematic review by Barbee et al. (2018). Therefore, it reinforces the use of these measures in identifying individuals with noise-induced synaptopathy.

    Age-induced synaptopathy

    Behavioral domain

    Prendergast et al. (2019) did not find a significant difference in SPiN scores between young and old individuals with near-normal hearing. Several studies have examined the effect of aging on suprathreshold auditory processing skills. However, in the majority of these studies, older individuals also had concomitant high-frequency hearing loss. The presence of hearing loss prevents drawing any firm conclusions between aging and auditory processing. Two studies included in the current systematic review examined the perception of amplitude modulation in individuals with suspected age-induced synaptopathy. Prendergast et al. (2019) reported no age-related differences in amplitude modulation and spectral modulation detection whereas Grose et al. (2019) reported that amplitude modulation detection thresholds improved with increasing age. These findings suggest that there is little effect of aging on temporal and spectral modulation detection. Further, tone perception in noise was found to be effective in predicting hidden hearing loss in older individuals who otherwise had near-normal thresholds in conventional pure tone audiometry (Ralli et al., 2019).

    Electrophysiological domain

    ABR results are equivocal in age-induced synaptopathy (Grose et al., 2019; Prendergast et al., 2019). Grose et al. compared younger and older individuals and reported a reduction in wave I amplitude as well as ratio of the amplitude of wave I to wave V with increase in age. However, ABR was not reported to be an indicator of synaptopathy by Prendergast et al. (2019). These authors also studied EFR in the same population and reported that no significant differences were observed in the EFR amplitude between younger and older individuals.

    The number of studies conducted in age-induced synaptopathy is relatively lesser compared to noise-induced synaptopathy. Therefore, it is difficult to draw stronger conclusions about various tests in detecting age-induced synaptopathy.

    Synaptopathy in individuals with tinnitus

    Behavioral domain

    In-normal hearing individuals with tinnitus, Kara et al. (2020) performed extended high-frequency audiometry and found a significant difference in the thresholds compared to the control group without tinnitus. None of the studies on age-induced synaptopathy included in this systematic review reported high-frequency audiometry. Lefeuvre et al. (2019) assessed the hearing thresholds of individuals with and without tinnitus using 1 dB precision in intensity and 1 Hz precision in frequency. The authors opine that when tinnitus is associated with hearing loss on a narrow frequency range, conventional audiogram might fail to reflect this hearing loss leading to the possibility of hidden hearing loss. Therefore, use of high-definition audiometry with 1 dB precision in intensity and 1 Hz precision in frequency increases the possibility of identification of hidden hearing loss in addition to determining the characteristics of tinnitus. With this procedure, about 80% of individuals in the tinnitus group had abnormal results (micro notch or slope in the audiogram), that were otherwise not reflected in the conventional audiometry. They interpreted this finding as evidence for hidden hearing loss in individuals with tinnitus. Similar results were reported by other studies in individuals with King-Kopetzky syndrome, wherein high-resolution audiogram revealed notches between 500 and 3000 Hz, which was otherwise missed in the conventional audiogram (Zhao & Stephen, 1999).

    Results of SPiN performance in individuals with tinnitus remain equivocal. Kara et al. (2020) reported that the SPiN scores were affected and correlated with other synaptopathy measures in individuals with tinnitus. However, Guest et al. (2019) reported that tinnitus was not associated with reduced SPiN scores. Furthermore, Guest et al. did not find any electrophysiological and physiological evidence of cochlear synaptopathy in their cohort of tinnitus patients. The tinnitus group in Kara et al.’s study had significantly higher high-frequency hearing thresholds than the control group. In addition, participants in Kara et al.’s study were older than that of Guest et al. Therefore, poor SPiN scores in Kara et al.’s study may be due to elevated thresholds and older age.

    Four studies included in this review have assessed suprathreshold psychophysical abilities in normal-hearing individuals with tinnitus. Epp et al. (2012) assessed the DLI in individuals with and without tinnitus and reported that DLI in the tinnitus frequency range were elevated in individuals with tinnitus. Similarly, amplitude modulation detection was found to be affected in normal-hearing individuals with tinnitus compared to their control group (Paul et al., 2017). The TEN test was administered in two studies. Although Marmel et al. (2020) did not find the masked threshold to correlate with synaptopathy, Kara et al. (2020) revealed that the TEN test showed dead regions in 75% of normal-hearing individuals with tinnitus. Kara et al. (2020) report that the presence of a dead region might indicate the involvement of IHCs in the perception of tinnitus.

    Physiological domain

    Guest et al. (2019) did not find any significant deviance in the MEMR threshold in individuals with tinnitus. They attribute the discrepancy in results between this study and Wojtczak et al.’s study on noise-induced synaptopathy to the methodological differences between the two studies. Although Guest et al.’s study used 226 Hz probe tone and tonal elicitors to measure MEMR threshold, Wojtczak et al. used wideband probe signal and wideband elicitors to measure MEMR amplitude.

    Electrophysiological domain

    Among the studies related to synaptopathy in individuals with tinnitus, Kara et al. (2020), reported an increased SP/AP ratio in individuals at risk for cochlear synaptopathy. ABR results were equivocal in individuals with tinnitus (Guest et al., 2017; Schaette & McAlpine, 2011; Shim et al., 2017). Shim et al. (2017) reported that the origin of tinnitus is multifactorial, and the perception of tinnitus might be due to effects other than synaptopathy. Further, they used a within-subject design, wherein the ABR results were compared between the tinnitus ear and the non-tinnitus ear in individuals with unilateral tinnitus. A few human studies on normal-hearing individuals with tinnitus (Paul et al., 2017) revealed that the neural temporal coding is affected in individuals with cochlear synaptopathy and reflected in EFF. However, Guest et al. (2017) failed to show significant effect of aging on EFR.

    The results of various tests in normal-hearing individuals with tinnitus are heterogenous. This could be attributed to the multifactorial origin of tinnitus and that synaptopathy may or may not be the sole cause of tinnitus.

    Animal studies

    Noise-induced synaptopathy

    Physiological domain

    The animal studies on noise-induced synaptopathy (Fernandez et al., 2020; Hickman et al., 2018; Lobarinas et al., 2017; Morgan et al., 2019; Shaheen et al., 2015; Song et al., 2016; Valero et al., 2016, 2018; Valero et al., 2017) measured OAEs one-day post noise exposure and after a recovery period of 2–4 weeks. Though the DPOAEs were reduced 1 day post noise exposure due to temporary threshold shift, complete recovery was seen in further evaluations.

    Animal studies also reported elevated MEMR threshold and reduced MEMR magnitude in noise-induced synaptopathic mice (Valero et al., 2016, 2018). This could be attributed to the involvement of low spontaneous rate fibers in the afferent neurons of the MEMR pathway (Kobler et al., 1992; Liberman & Dodds, 1984). Since synaptopathy is believed to affect the low spontaneous rate fibers, MEMR might be affected in individuals with synaptopathy.

    Electrophysiological domain

    At the brainstem level, ABR and EFR are studied extensively in individuals with suspected hidden hearing loss. Unequivocal findings were observed in various species of animals. Thirteen studies on noise-induced synaptopathy (Bakay et al., 2018; Chen et al., 2019; Fernandez et al., 2020; Hickman et al., 2018; Lobarinas et al., 2017; Liu et al., 2019; Morgan et al., 2019; Mulders et al., 2018; Shaheen et al., 2015; Song et al., 2016; Valero et al., 2016, 2018; Valero et al., 2017) reported ABR to be an effective tool in diagnosing synaptopathy. The general finding of these studies is that a temporary threshold shift in ABR is seen 24 h post noise exposure, which recovers completely by about 2–4 weeks. Though the ABR thresholds return to normal, suprathreshold wave I amplitude showed only partial recovery. These findings were supported by the reduction in the number of ribbon synapses, as revealed by histopathology. The findings of histopathology revealed that the neural density and synapse counts were reduced post noise exposure. However, Morgan et al. (2019) reported that repeated noise exposure failed to show signs of synaptopathy. Studies on animal participants also indicated that EFR failed to show noise-induced cochlear synaptopathy (Chen et al., 2019).

    Age-induced synaptopathy

    Physiological domain

    Animal studies on age-induced cochlear synaptopathy (Parthasarathy & Kujawa, 2018) also reported that the synapse loss was observed before the damage to hair cells. Thus, it can be concluded that the OAEs are unaffected in cases of cochlear synaptopathy except where synaptopathy accompanies hearing loss.

    Electrophysiological domain

    Three studies on age-induced synaptopathy reported ABR to be an effective tool in diagnosing synaptopathy (Cai et al., 2018; Muniak et al., 2018; Parthasarathy & Kujawa, 2018). With increase in age, the ABR amplitude showed a slow recovery post noise exposure. These findings were supported by the reduction in the number of ribbon synapses, as revealed by histopathology. However, EFR failed to show age-induced cochlear synaptopathy (Parthasarathy & Kujawa, 2018).


      Conclusions Top


    The present study reviewed 46 articles on cochlear synaptopathy, among which 30 studies included human participants and 16 included animal participants. The possibility of noise-induced synaptopathy was assessed in 30 studies; age-induced synaptopathy in 6 studies; and synaptopathy in normal hearing individuals with tinnitus in 10 studies. Although the results are convincing in animals, human studies did not provide conclusive evidence of cochlear synaptopathy. The current systematic review identified extended high-frequency audiometry, temporal processing tests (GDT and modulation detection), and SPiN as promising measures of cochlear synaptopathy, especially in individuals with cochlear synaptopathy due to occupational noise exposure. However, there is little evidence for the effect of recreational noise or environmental noise exposure on any behavioral measures. MEMR can be a potential physiological tool in assessing hidden hearing loss due to noise exposure. In terms of electrophysiology, ABR wave I amplitude growth and SP/AP ratio of ECochG proved to be potential measures of synaptopathy. ABR was found to be more effective when recorded in horizontal montage using tiptrode. Further, working memory tasks could be yet another effective tool to assess noise-induced synaptopathy. Although tinnitus was shown to affect extended high-frequency hearing thresholds, the effect of aging and tinnitus on other behavioral measures as well as ABR are not conclusive. Overall, the results of this review indicate that the results of behavioral, physiological and electrophysiological measures are more consistent in noise-induced synaptopathy than synaptopathy due to aging or in individuals with tinnitus. Hence, cautious interpretation of the results with due consideration to the population under study is warranted.

    Acknowledgement

    The authors acknowledge with gratitude the Director, All India Institute of Speech and Hearing, Mysuru for permitting to conduct the study at the institute. The authors also acknowledge the University of Mysuru. We acknowledge the support of DST [grant number SR/CSRI/2017/61].

    Financial support and sponsorship

    Not applicable.

    Conflicts of interest

    There are no conflicts of interest.

    Appendices

    Appendix 1: PRISMA 2009 checklist



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    Appendix 2: Summary of human studies on synaptopathy



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    Summary of animal studies on synaptopathy



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    Appendix 3: Quality assessment of human studies



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    Quality assessment of animal studies



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